The objective of this proposal is to identify the physiological functions of a newly identified vasoactive peptide, Adrenomedullin (Adm). Preliminary studies have suggested a variety of functions for Adm. Most acclaimed is Adm's potential role in blood pressure regulation since it has been found at markedly elevated plasma levels in patients with multiple forms of hypertension. Other studies have implicated Adm in such physiological processes as natriuresis, regulation of aldosterone, ACTH and renin secretion, thirst, embryonic implantation, and cellular proliferation. To examine the function of Adm within an intact physiological milieu, a series of mice will be generated that contain between 0-4 copies of the Adm gene by using the methods of homologous recombination in embryonic stem cells and the mechanisms of gene disruption and gene duplication. The specific aims of this proposal are to: 1) determine the essential biological functions of the Adm gene within an intact physiological milieu by characterizing a knockout mouse model and 2) determine the effects of varying Adm gene expression on blood pressure and related cardiovascular parameters by characterizing a "gene titration" of Adm. Elucidation of the physiological functions of Adm will enhance our general understanding of this new peptide. Moreover, determining the role of Adm in blood pressure regulation will lead to a better understanding of blood pressure homeostasis and may lead to new genetic and pharmacological strategies for the prevention or therapy of hypertension.